1. Field of the Invention
The present invention relates to a method of treating cranial fluid volume dysfunctions including edema, hydrocephalus and glaucoma.
2. Description of the Background Art
Because the brain is encased within a rigid skull and lacks a true lymphatic drainage system, it is critically vulnerable to damage from edema. However, compared with peripheral tissues, relatively little is known about intracranial regulation of water and electrolytes. Extracellular fluid movement into and out of the brain occurs primarily at the level of the blood-brain barrier (capillary endothelium), blood-cerebrospinal fluid (CSF) barrier (choroid plexus epithelium), and CSF outflow system (dural sinus/arachnoid villae). Smith et. al., J. Neurochem., 37:117 (1981); Johanson, Encycl. Neurosci., (G. Adelman, Ed.) Birkhauser Boston, in press.
Pathological conditions associated with fluid accumulation in the cranium include cerebral (brain) edema and hydrocephalus, among others. Cerebral edema is a distinct and separate pathological entity from peripheral edema, and may result from a variety of causes such as stroke (including hemorrhage), anoxia, trauma, tumor, or infection. In some cases (e.g., pseudotumor cerebri or Reye's syndrome) the cause is as yet unknown.
The components of the intracranial compartment are brain, cerebrospinal fluid, and blood. Because the skull limits the total intracranial contents, the volume of the compartment is compromised with expanding lesions within the cranial cavity. The brain is virtually incompressible, so the CSF and blood serve as the main buffers of changing intracranial volume. Increases in intracranial pressure may be caused by such diverse pathologic processes as head trauma, cerebral hemorrhage, encephalitis, and brain edema. Increased intracranial pressure may not be harmful in itself, but secondary damage results either as a consequence of precipitously decreased global cerebral perfusion or herniation of brain tissue. Approximately 50% of patients who die as a result of closed head injury do so because of uncontrolled elevations in intracranial pressure.
The ability of cerebral vasculature to dilate or constrict in response to decreased or increased perfusion pressure, respectively, may also be impaired by head trauma. Occasionally, large-vessel vasospasm may also occur after acute head injury.
Intracranial tumors often cause edema of the surrounding brain tissue. Circulatory slowing and altered permeability of vessels lead to local vasogenic edema of the brain. The increased brain volume occasioned by the tumor and surrounding edema may raise the pressure in one of the cranial compartments to the point that the brain tissue is displaced into an adjacent compartment. In this way brain herniations occur. Regional edema causes a rapidly evolving impairment of the function of the part of the brain involved.
Pathologic intracranial infections may also lead to intracranial edema. The early reaction to bacterial invasion of the brain includes localized inflammatory necrosis and edema. Persistence or progression of high intracranial pressure may cause deepening coma and threat of herniation.
Hydrocephalus is a condition of increased intracranial pressure caused by obstruction to the movement or impairment of the reabsorption of cerebrospinal fluid (CSF). This can result from congenital defects, infections, cerebral hemorrhage, inflammatory conditions, and other conditions. Cerebrospinal fluid is normally secreted by the choroid plexus, a tissue located in the cerebral ventricles.
Glaucoma is a condition of the eye associated with high pressure due to an impediment in the outflow of the aqueous fluid (aqueous humor), which is normally secreted by the ciliary process (a tissue similar in function to the choroid plexus). In 90% of cases the cause is unknown, while in 5%, the condition is secondary to some disease process that blocks the outflow channels. Glaucoma occurs in 2% of all patients over 40; it may be asymptomatic and unrecognized before it progresses to rapid vision loss. The normal pressure is about 15 mmHg. Pressures of 20-30 mmHg may damage the optic nerve and lead to blindness.
Prior to the present invention, methods of treating cerebral edema have included administration of urea, mannitol, or cortisone derivatives. These treatments are often inadequate and patients can go on to develop severe neurological sequelae or even death. Even surgical fluid drainage (ventriculostomy) often can not prevent these sequelae. Pharmacological treatment of hydrocephalus has also been quite disappointing. Patients often require a permanent surgical shunt, a procedure which has serious side effects, including infection and subdural hematoma. In the area of glaucoma, some advances have been made with the introduction of beta-adrenergic blockers. However, these agents can have serious pulmonary and cardiovascular side effects, including asthma and congestive heart failure.
Recently, it has been suggested that a group of peptides, released from atrial cardiac myocytes, are key hormones for regulating fluid volume in the periphery. Cantin and Genest, Endocrine Rev., 6:107 (1985); deBold, Science, 230: 767 (1985). These peptides are known as atrial natriuretic peptides, atrial natriuretic factors (ANF), or atriopeptins (ANP), and have been isolated from a variety of species, including man. In response to fluid overload, atriopeptins are released into the circulation and cause rapid diuresis and natriuresis through both direct and indirect effects on the kidney. Atriopeptins are also known to induce systemic vasodilation through an endothelial-independent mechanism. Windquist, Life Sci., 37:1081 (1985). Reports of studies in peripheral tissue suggest that the atriopeptin receptor occupancy is associated with the intracellular production of guanosine 3',5'-monophosphate (cyclic GMP). Waldman et. al., J. Biol. Chem., 259:14332 (1984); Winquist et. al., Proc. Natl. Acad. Sci. USA, 81: 7661 (1984). Atriopeptin receptors have been identified by autoradiographic studies in kidney and (peripheral) vasculature as well as in other tissues including brain (hypothalamus and circumventricular organs), pituitary, intestine, adrenal, and ciliary body. Napier et al., Proc. Natl. Acad. Sci. (USA), 81:5946 (1984); Gibson et al., J. Neurosci., 6:2004 (1986).
Many hormones act through "second messengers" such as cyclic AMP (cAMP) or cyclic GMP (cGMP). An accepted model of hormone action involves the binding of a hormone to a hormone-specific cell membrane-bound receptor which activates a hormone-sensitive adenylate (for cAMP) or guanylate (for cGMP) cyclase to a form capable of converting ATP (or GTP) in the cytoplasm of the cell into cAMP (or cGMP). The cAMP (or cGMP) then relays the signal brought by the hormone from the membrane to the interior of the cell. Agonists of the hormone are, by definition, capable of eliciting the same response (see, for example, Nathanson and Greengard, Scientific American, 237:108-119 (1977) for a discussion involving cyclic nucleotides).
Once formed inside cells, cAMP and cGMP are broken down by a group of enzymes called cyclic nucleotide phosphodiesterases (hereafter called phosphodiesterase). Pharmacological inhibition of phosphodiesterase results in prolonged and augmented levels of cAMP and cGMP within cells, and can cause physiological responses similar to those of the original hormone.